Spasmodic dysphonia (SD) is a primary focal dystonia characterized by selective impairment of voluntary voice control during speech production. Despite recent progress in characterization of clinical features and brain abnormalities in SD, the causes and pathophysiology of this disorder remain unclear. Specifically, there is a fundamental gap in understanding how variations in the causative gene expression lead to variations in brain abnormalities in different SD phenotypes (e.g., familial, sporadic, adductor, abductor). Continued existence of this gap represents an important problem because, until it is filled, full characterization of SD phenotypes, assessment of SD risk in families, and the design of novel therapeutic approaches for these patients will remain largely unattainable. Our long-term goal is to determine the causes and pathophysiology of SD and to develop new diagnostic and treatment options for this disorder. The objective of this application is to identify SD phenotype-specific brain abnormalities associated with genetic risk factors using a novel approach of combined imaging SD genetics and next-generation DNA sequencing. Our central hypothesis is that functional and structural brain networks in different SD phenotypes (sporadic vs. familial and adductor vs. abductor SD) will exhibit features of shared and distinct alterations due, in part, to association with shared and independent genetic susceptibility factors. Our central hypothesis has been formulated, in large part, on the basis of our preliminary data. The rationale for the proposed research is that identification of SD phenotype- specific brain abnormalities and the associated genetic susceptibility risk factors will establish a strong scientific framework for characterization and development of diagnostic biomarkers for detection and evaluation of SD patients as well as for screening of persons at-risk. Using a comprehensive approach of multi- modal neuroimaging, next-generation DNA sequencing technology and clinico-behavioral testing, our central hypothesis will be tested by pursuing three specific aims: (1) determine the SD phenotype-specific organization of functional brain networks; (2) establish the measurements of SD phenotype-specific structural brain abnormalities; and (3) identify genetic factors associated with different SD phenotypes and correlate these factors with the functional and structural imaging markers. This research is innovative, because it uses a transdisciplinary approach as a tool for discovery of the mediating neural mechanisms that bridge the gap from DNA sequence to pathophysiology of SD. The proposed research is significant because it is the first step in a continuum of SD research that is expected to vertically advance and expand the understanding of the mechanistic aspects of brain function affected by risk gene variants. Ultimately, the results of these studies are expected to advance our knowledge for enhancement of SD clinical management and identification of novel approaches to new treatment options in these patients. PUBLIC HEALTH RELEVANCE: PROJECT NARRATIVE The proposed research aims to determine the extent of relationship between genetic risk factors and brain abnormalities in SD that can be used reliably for discovery of associated genes and neural integrity markers. The proposed research is relevant to public health because the elucidation of the mechanistic aspects of brain function affected by risk gene variants is ultimately expected to lead to establishment of enhanced criteria for clinical management of SD, including its detection, diagnosis and treatment. Thus, the proposed research is relevant to the part of NIH's mission that pertains to developing fundamental knowledge that will help to reduce the burdens of human disability.